EP2205238A2 - Combination therapy related to serotonin dual action compounds - Google Patents
Combination therapy related to serotonin dual action compoundsInfo
- Publication number
- EP2205238A2 EP2205238A2 EP08833434A EP08833434A EP2205238A2 EP 2205238 A2 EP2205238 A2 EP 2205238A2 EP 08833434 A EP08833434 A EP 08833434A EP 08833434 A EP08833434 A EP 08833434A EP 2205238 A2 EP2205238 A2 EP 2205238A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- htp
- amine
- compound
- amount ranging
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to combination therapies and pharmaceutical compositions with improved efficacy comprising a combination of 5 ⁇ hydroxytryptophan and a serotonin reuptake inhibitor which binds to an allosteric site of the serotonin transporter.
- 5-hydr ⁇ xytryptophan is the direct precursor to serotonin (5- hydroxytryptamine; 5-HT), In vivo, 5-HTP is decarboxyiated to produce 5- HT. 5-HT levels in the brain are dependent on levels of 5-HTP in the central nervous system (CNS). No transport molecules are necessary to transport 5-HTP across the biood-brain barrier, 5-HTP has been clinically shown to increase production of serotonin in the brain and therefore 5-HTP administration has been suggested as a treatment for patients with mild or moderate depression (for review, see Meyers, S., Alt ⁇ rn Med Rev. 2000 Feb. 5 ⁇ 1):64-71 ; and Birdsaii, T.C., Altem Med Rev, 1998 Aug; 3 ⁇ 4 ⁇ :271- SO).
- Serotonin reuptake inhibitors have become first choice therapeutics in the treatment of affective disorders, especially depression, because they are effective, well tolerated and have a favorable safety profile compared to the classic tricyclic antidepressants.
- 5-HTP monotherapy has been associated with gastrointestinal (nausea, vomiting, diarrhea) and psychopathoSogicai (acute anxiety state, hypomania) side effects in open studies with human patients (Zmilacher, K., Battegay, R. and Gastpar, M.,, Neuropsychobiology. 1988, 20(1):28 ⁇ 35; Gijsman, HJ., et a!., J CHn Psychopharmacol. 2002 Apr, 22(2); 183-9).
- 5-HTP administration has been implicated as a possible cause of Eosinophilia-Myalgia Syndrome (for review, see Das. YT. , et al., Toxicol Lett. 2004 Apr 15; 150 ⁇ 1):111-22.).
- One approach to managing these risks of side effects may be to lower the dose of 5-HTP.
- SRSs possible side effects to be balanced against the known benefits of SRIs and to be managed may include sexual dysfunction and sleep disturbances.
- Many patients experience delayed onset of a therapeutic effect during SRl monotherapy.
- Further clinical studies on depression and anxiety disorders indicate that more than 30% of patients treated with SR! monotherapy as a class are non-responsive.
- patients may benefit from administration of a Sower dose of 5-HTP.
- Patients may also benefit from administration of a Sower dose of an SRl.
- patients that do not respond to SRSs may benefit from a combination therapy of an SRS and 5-HTP.
- Such combination therapy includes Sower doses of either SRI or 5-HTP, yet may achieve greater efficacy or earlier onset of therapeutic effect than with SRI or 5-HTP monotherapy.
- Such combination therapy is particularly beneficial when the SRI binds to an aiSosteric site of the serotonin transporter (SERT).
- SERT serotonin transporter
- An objective of the present invention is to provide a pharmaceutical composition comprising (i) 5-hydroxytrytophan and (ii) 2- ⁇ 6-Fluoro-1H- indol ⁇ 3-ylsulfanyl) ⁇ benzyt] ⁇ methyf-amine.
- Another objective of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising (i) 5-hydroxytryptophan in an amount ranging from about 1 mg to about 75 mg; and (ii) a serotonin reuptake inhibitor that binds to an aifosteric site of the serotonin transporter; 2 ⁇ (6-Ruoro-1H-ind ⁇ i- 3-ylsulfanyi)-benzyi]-methyl-amine.
- FIG. 1 Firing rate histogram representative of a spontaneousiy firing serotonin-containing neuron in the dorsal raphe of an anesthetized rat. Injection of a low threshold dose of 5-HTP (25 mg/kg) (left arrow) reduces cell firing rate. A further decrease is observed following a second injection of 25 ⁇ g/kg of Compound Ii 1 2-(6-F!uoro-1 H-indol-3-y!suifany!-benzylJ- methyl-amine (right arrow),
- FIG. 2 Firing rate histogram representative of a spontaneously firing serotonin-containing neuron in the dorsal raphe of an anesthetized rat.
- Compound Ii 2 ⁇ (6-FSuoro-1 H-indol ⁇ 3-ylsu!fanyl)-benzyl3-methyS-amine (left arrow), is administered prior to 25 mg/kg 5-HTP (middle arrow) in experiments simiSar to those presented in Figure 1.
- the second injection (5-HTP) greatiy decreased eel! firing.
- FIG 3 Graphical summary of the combination dosing of Compound H and 5-HTP on dorsal raphe cell firing.
- WA Y- 100835 a selective 5-HTi A antagonist
- FIG 3 Graphical summary of the combination dosing of Compound H and 5-HTP on dorsal raphe cell firing.
- the combination of this SR! and this 5-HT precursor produces an effect on neuronal activity that is greater than that achieved by simply adding the individual dose effects.
- the combination of 5-HTP injected after Compound S! has a significantly greater effect on cell firing rate than 5-HTP alone ( ** p ⁇ 0.01).
- the effect of 5-HTP followed by injection of Compound Sl on cell firing rate is significantly greater than the effect of Compound Il alone ( ** p ⁇ 0.01).
- Statistical analysis was performed on data collected from six different rats.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising 5-hydroxytryptophan and a serotonin reuptake inhibitor that binds to an alSosteric site of the serotonin transporter, for example 2-( ⁇ -Fluoro-1H- indol-3-ylsulfany! ⁇ benzyi]-methyS-amine.
- SRI serotonin reuptake inhibitor
- aiiosteric modulator shall mean an SRI that binds to an aiiosteric site of the serotonin transporter (SERT). Such compounds are also called aiiosteric serotonin reuptake inhibitors (ASRfs).
- SERT serotonin transporter
- ASRfs aiiosteric serotonin reuptake inhibitors
- the aiiosteric modulator binds to one or more aiiosteric sites of the SERT.
- the alSosteric modulator binds to the allosteric site of the SERT capable of binding 2 ⁇ 6- Ru ⁇ ro-1 H ⁇ indol ⁇ 3-ylsulfanyl)-benzyl]-methyl-amine.
- 5-hydroxytryptophan is an aromatic amino add naturally produced in the body from amino acid L-tryptophan, 5-HTP is the direct precursor to 5-HT.
- the formula of 5-HTP is shown below as Formula I.
- 5-HTP is also known as 2 ⁇ amino ⁇ 3-(5-hydr ⁇ xy-1 H-jndol-3-yl)-propanoic acid ⁇ C 1 1H 12 N 2 O 3 ).
- 5-HTP and “5-hydroxytryto ⁇ han” are intended to include any form of the amino acid 5- hydroxytryptophan, including the base (zwitter ion), pharmaceutically acceptable salts, hydrates or solvates of the base or salt, as well as anhydrates, and also amorphous, or crystalline forms.
- pharmaceutically acceptabie salts includes salts with pharmaceutically acceptable acids or bases.
- such salts may be formed with pharmaceutically acceptable bases, particularly strong bases such as sodium potassium or ammonium hydroxide.
- Such salts of 5-HTP may also be formed with pharmaceutically acceptable acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, maleic acid, oxalic acid, tartaric acid and the like.
- 5-HTP may be used in the form of an acid addition salt, or in the form of a zwitter ion hydrate, zwitter ion monohydrate, or zwitter ion anhydrate.
- 5-HTP may be in a racemic mixture or as the substantially pure D-enantiomer, D-5-hydroxytryptophan, or as the substantially pure L-enantiomer, L-5-hyc!roxytryptophan.
- One aspect of the present invention relates to a pharmaceutical composition comprising 5-HTP for use in a combination therapy with an SRL
- Another aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (i) 5-hydroxytryptophan in an amount ranging from about 1 mg to about 75 mg; and (ii) 2 ⁇ (6-Fluoro-1 H-indoi ⁇ 3 ⁇ ylsulfanyl) ⁇ benzyl]-methyl ⁇ amine.
- 5-HTP may be used to augment and/or provide an earlier onset of the therapeutic effect of serotonin reuptake inhibitors, such as a ⁇ osteric modulators.
- lower doses of 5-HTP when used in combination therapy may augment and/or provide an earlier onset of the therapeutic effect of an altosteric modulator, in one embodiment of the invention, 5-HTP ⁇ n an amount ranging from about 1 mg to about 75 mg is coadministered with 2-(8-Fluoro-1 H-indol-3-ylsulfa ⁇ y!)-benzyi]-methyl- amine.
- 5-HTP in an amount ranging from about 3 mg to about 50 mg is coadministered with 2- ⁇ 8- Fluoro-1 H-indol-3-ylsulfanyl)-ben2y!]-methyl-amine.
- 5-HTP in an amount ranging from about 10 mg to about 50 mg is coadministered with 2- ⁇ 6 ⁇ Fluoro ⁇ 1H ⁇ indol ⁇ 3- yisuifanyl)-benzyl]-methyl-amine.
- “augmenting” shall mean improving the therapeutic effect and/or potentiating the effect of an SRI.
- 2- ⁇ 6-Fluoro-1 H-indol-3-ylsulfanyS)-benzyij-methyS- amine is an SRl which forms an embodiment of the present invention, or a pharmaceutically acceptable salt of any of these compounds.
- the formula of 2-(6-Fluoro-1 H-inc!o!-3-yls ⁇ lfanyl)-benzy!]-methyl-ami ⁇ e is shown as Formula II.
- the compound of Formula H 5 hereinafter referred to as Compound H exerts an inhibitory effect at both the serotonin transporter (SERT) and the norepinephrine transporter (NET), as measured by in vitro reuptake inhibitory potency, and, as such, is considered a serotonin-norepinephrine reuptake inhibitor (SNRi).
- SERT serotonin transporter
- NET norepinephrine transporter
- SNRi serotonin-norepinephrine reuptake inhibitor
- norepinephrine also means noradrenaline.
- Compound Il meets the definitions of an SRi, an SNRI, and an ASRI.
- Compound il mentioned above may be used in the form of the free base or in the form of a pharmaceutically acceptable salt, such as an acid addition salt, the latter being obtainable by a reaction of the base form with an appropriate acid.
- 2-(6 ⁇ Fiuoro ⁇ 1H ⁇ indol-3 ⁇ yisuifanyO-benzylj-methyi-amine is in the form of pharmaceutically acceptable salt.
- 2-(6 ⁇ Ruoro ⁇ 1 H ⁇ indoJ-3 ⁇ ySsulfanyl)-benzy!]-methyl ⁇ amine may be used in the form of the L ⁇ +) ⁇ hydrogen tartrate salt.
- such salts may include pharmaceutical acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
- Acid addition salts include salts of inorganic acids as well as organic acids. Also intended as pharmaceutical acceptable acid addition salts are the hydrates, which trie present compound, is able to form. Examples of suitable inorganic acids and organic acids are described in WO05/061455A1 , which is hereby incorporated by reference in its entirety.
- Antidepressant compounds that demonstrate potent inhibition of serotonin reuptake also inhibit dorsal raphe neuronal firing rates (Rigdon, GC and Wang, CM 1 Drug Development Research 1991 , 22: 135-140).
- SR ⁇ s dorsal raphe neuronal firing rates
- co-administration of 5-HTP and an SRI, namely Compound IS, or a pharmaceutically acceptable salt thereof is shown herein to have a greater effect on dorsal raphe neuronal firing than the administration of either compound alone.
- the surprising effects of combined administration of 5- HTP and this SRi are determined to be synergistic, and not additive, thereby providing improved therapeutic potential.
- lower doses of 5-HTP than normally used in monotherapy may be used in combination with a dose of Compound Ii normally used in monotherapy to augment the 5-HT output and thereby may provide an earlier onset of the therapeutic effect.
- the amount of 5-HTP to be used in combination therapy may range from about 1 to about 75 mg per day, such as from about 3 to about 50 mg per day, or from about 10 to about 50 mg per day.
- Pharmaceutical compositions of the present invention may therefore comprise from about 1 to about 75 mg, such as from about 3 to about 50 mg, or from about 10 to about 50 mg 5-HTP.
- a "therapeutically effective amount" of a compound means an amount of a compound sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its symptoms and/or complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It is understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is ail within the ordinary skills of a trained physician.
- the pharmaceutical composition comprises a therapeutically effective amount of 2-(8-F!uoro-1H-indol-3- ylsulfanyf)-benzyl]-nnethyi ⁇ amin ⁇ . in a further embodiment, the pharmaceutical composition comprises from 0.1 mg to 50 mg of 2- ⁇ 6- Fluoro-1 H ⁇ indoi-3 ⁇ ySsuSfany!-benzy!]-methyi ⁇ amine. Also included in the present invention is the administration of such pharmaceutical composition to a patient in need thereof, so that the daily dose ranges of 2-(6-F!uoro- 1 H-indo!-3-ylsulfanyS)-benzyl3-methyi ⁇ amine are 0.1 mg to 50 mg per day.
- “subeffective dose” shall mean a dose in an amount less than the lowest dose that is administered to achieve a clinicai result as a monotherapy.
- the pharmaceutical composition comprises 2-(6-Fluoro-1 H-indo!-3-ylsulfanyl)-benzyl ⁇ -methyl-ami ⁇ e in an amount less than 50 mg and 5-HTP in an amount ranging from about 1 mg to about 600 mg.
- the pharmaceutical composition comprises 2- ⁇ 6-Fluoro-1 H-indoi-3-ylsulfanyl)- benzyiJ-methyS-amine in an amount less than 50 mg and 5-HTP in an amount ranging from about 25 mg to about 300 mg.
- the pharmaceutical composition comprises 2- ⁇ 6-F!uoro-1 H-indol-3-ylsulfanyl) ⁇ benzyl]-methyl- amine in an amount less than 50 mg and 5-HTP in an amount ranging from about 50 mg to about 200 mg.
- the pharmaceutical composition comprises 2-(6-Fluoro-1 H-i ⁇ doi-3-yls ⁇ lfanyl)- benzyij-rnethyl-amine in an amount from about 0.1 mg to about 49.9 mg.
- the amount of 5-HTP to be used in combination therapy may range from about 1 mg to about 600 mg per day, such as from about 25 mg to about 300 mg per day, or from about 50 mg to about 200 mg per day.
- Pharmaceutical compositions of the present invention may therefore comprise from about 1 mg to about 600 mg, such as from about 25 mg to about 300 mg, or from about 50 mg to about 200 mg 5-HTP.
- one embodiment of the present invention includes a pharmaceutical composition comprising a subeffective close of Compound ii and 5-HTP 1 wherein the composition comprises 5-HTP in an amount ranging from about 1 mg to about 600 mg, from about 25 mg to about 300 mg, or from about 50 mg to about 200 mg. Also included in the present invention is the administration of such pharmaceutical compositions to a patient in need thereof, so that the daily dose ranges of 5-HTP are from about 1 mg to about 600 mg per day, or about 25 mg to about 300 mg per day, or about 50 mg to 200 mg per day
- Aromatic amino acid decarboxylases that degrade 5-HTP to serotonin are widely distributed throughout the body, A peripheral decarboxylation inhibitor can be administered in combination with 5-HTP to prevent the degradation of 5-HTP to serotonin.
- the pharmaceutical composition may further comprise a peripheral decarboxylation inhibitor.
- Peripheral decarboxylation inhibitors include, but are not limited to, carbidopa, L- ⁇ -methyldopa, monofiuoromethyldopa, difluoromethyfdopa and bensera2ide.
- compositions of the present invention may contain carbidopa in an amount ranging from about 100 mg to about 150 mg.
- the pharmaceutical compositions described herein may be administered in any suitable way, e.g. orally or parentally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection, in one embodiment of the present invention, the composition is administered in the form of a solid pharmaceutical entity, suitably as a tabSet or a capsule or in the form of a suspension, solution or dispersion for injection.
- tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabietting machine.
- adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatin, gums, and the like.
- Other adjuvants or additives such as colorings, aroma, preservatives, etc. may aiso be used provided that they are compatible with the active ingredients.
- the pharmaceutical compositions can be administered as part of the claimed invention as an oral dose form, such as a solid dose form, typically tablets or capsules, or as a liquid oral dose form.
- the pharmaceutical compositions described herein are most conveniently administered in unit dosage forms such as tablets or capsules.
- such tablets or capsules may contain 5-HTP in amounts ranging from about 1 to about 600 mg, or from about 25 mg to about 300 mg, or from about 10 to 50 mg.
- an appropriate amount of 5-HTP and/or Compound ⁇ l, in salt form or base form is combined in an intimate admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form desired for administration.
- a pharmaceutically acceptable carrier which can take a wide variety of forms depending on the form desired for administration.
- Those pharmaceutical compositions may be in unitary dosage form suitable for administration orally, recially, percutaneously, or by parenteral injection.
- any of the usual pharmaceutical media such as water, glycols, oiis, alcohols, and the like, may be incorporated in the form of oral liquid preparations.
- Oral liquid preparations may be suspensions, syrups, elixirs, and solutions.
- any of the usual pharmaceutical media such as starches, sugars, kaolin, lubricants, binders, disintegrating agents, and the like, may be incorporated in the form of solid carriers.
- Oral solid preparations may be powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers would be employed.
- unitary dosage form means physicaily discrete units suitable as unitary dosages, each unit containing a predetermined quantity of 5-HTP and/or Compound H calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
- unitary dosage forms are tablets ⁇ including scored coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, and the like, and combinations thereof.
- 5-HTP may be administered before, during or after the administration of Compound I!, provided that the time between administration of 5-HTP and the administration of Compound I! is such that ingredients are allowed to act synergistically on the central nervous system.
- a single composition containing both Compound Il and 5-HTP may be particularly convenient.
- the serotonin reuptake inhibitor and 5-HTP may be administered separately in the form of suitable compositions.
- Such pharmaceutical compositions may further comprise a peripheral decarboxylation inhibitor.
- the compositions may be prepared as described hereinabove.
- such compositions may comprise Compound Il and a peripheral decarboxylation inhibitor, such as carbidopa.
- compositions may comprise 5-HTP and a peripheral decarboxylation inhibitor, such as carbidopa.
- a peripheral decarboxylation inhibitor such as carbidopa.
- Such compositions may be administered simultaneously, such as in a single tablet, and the like, or may be administered separately, such as in separate compositions or tablets, and the like.
- the present invention also comprises 5-HTP and Compound II, as a combination preparation for simultaneous, separate or sequential use in psychiatric drug therapy.
- Such compositions may comprise, for example, a kit comprising discrete unit dosage forms containing 5-HTP and discrete unit dosage forms of Compound II, all contained in the same container or pack, e.g. a blister pack.
- Such pharmaceutical compositions may further comprise a peripheral decarboxylation inhibitor.
- the invention relates to a kit comprising a dose of 2- ⁇ 6-Fiuoro ⁇ 1H-indoi-3 ⁇ ylsu!fanyS)-benzyl]-methyl-amine and 5-HTP.
- the invention relates to a kit comprising a dose of 2- ⁇ 8- Fluoro-1 H-indol-3-ylsulfanyl)-ben2y!]-methyl-amine and 5-HTP in an amount ranging from about 1 mg to about 800 mg, in an amount ranging from about 25 mg to about 300 mg or in an amount ranging from about 50 mg to about 200 mg.
- the invention relates to a kit comprising 2- ⁇ Fluoro- 1 H ⁇ indo!-3-ylsulfanyS)-benzyl]-methy! ⁇ amine, and 5-HTP in an amount ranging from about 1 mg to about 75 mg, in an amount ranging from about 3 mg to about 50 mg or in an amount ranging from about 10 rng to about 50 mg.
- the kit comprises 2 ⁇ 8 ⁇ F!uoro-1H ⁇ indol ⁇ 3- yisuifanyl)-benzyl]-methyS ⁇ amine in an amount ranging from about 0.1 mg to about 50 mg,
- the invention relates to a kit comprising 2 ⁇ (6-Fluoro- 1 H-indo! ⁇ 3-ylsulfany!-benzyl]-methyi ⁇ amine and 5-HTP, In some embodiments, the invention relates to a kit comprising 2- ⁇ 6 ⁇ Fluoro ⁇ 1H ⁇ indol-3-ylsulfany!-benzyt]-methyi-amine and 5-HTP in an amount ranging from about 1 mg to about 600 mg, in an amount ranging from about 25 mg to about 300 mg or in an amount ranging from about 50 mg to about 200 mg. !n some aspects, the kit further comprises a peripheral decarboxylation inhibitor,
- the invention reiates to the pharmaceutical compositions as described herein comprising 5-HTP and 2- ⁇ 0-Fiuoro-1 H-indol-3- yisuifanyl)-benzyl] ⁇ methyl-amine for use in combination therapy for the treatment of affective disorders
- the invention reiates to the pharmaceutical compositions as described herein comprising 5-HTP and 2- ⁇ 6 ⁇ Fluoro ⁇ 1 H-indol-3-ylsuifanyi)-benzyi]-methy!- amine for use in combination therapy for the treatment of depression
- the present invention relates to the pharmaceutical compositions as described herein comprising 5-HTP and 2- ⁇ 6-Fluoro-1H- indol ⁇ 3-yisu!fanyl)-benzyi]-methyS-amine for use in combination therapy for the treatment of anxiety disorders.
- Al! of the pharmaceutical compositions described herein may further comprise a peripheral decarboxylation inhibitor.
- the invention relates to a method for the treatment of a disease or disorder selected from the group consisting of an affective disorders, such as depression and anxiety disorders including genera! anxiety disorder, social anxiety disorder, acute stress disorder, post traumatic stress disorder, obsessive compulsive disorder, and panic anxiety in a living animal body, including a human, comprising administering to a subject in need thereof a therapeutically effective amount of Compound II, as the free base or a salt thereof, and 5-HTP.
- an affective disorders such as depression and anxiety disorders including genera! anxiety disorder, social anxiety disorder, acute stress disorder, post traumatic stress disorder, obsessive compulsive disorder, and panic anxiety in a living animal body, including a human
- the invention relates to use of Compound II, as the free base or a salt thereof, for the preparation of a pharmaceutical composition for the treatment of affective disorders, such as depression and anxiety disorders including genera! anxiety disorder, social anxiety disorder, acute stress disorder, post traumatic stress disorder, obsessive compulsive disorder, and panic anxiety.
- affective disorders such as depression and anxiety disorders including genera! anxiety disorder, social anxiety disorder, acute stress disorder, post traumatic stress disorder, obsessive compulsive disorder, and panic anxiety.
- the invention relates to the use of 5-HTP for the preparation of a pharmaceutical composition to be used in combination with 2-(6-Fluoro-1 H-indol-3-yisuifa ⁇ y!-benzyl]-methyi-amine.
- the invention relates to the use of 5-HTP for the preparation of a pharmaceutical composition useful for augmenting and/or providing an earlier onset of the therapeutic effect of 2- ⁇ 6-Fiuoro-1 H-indoS-3-ylsulfanyl)- benzyiJ-methyS-amine.
- the invention relates to a method of treatment of diseases or disorders responsive to an SR!, comprising administering 5- HTP and 2 ⁇ (6-FiuorG-1 H-indol-3 ⁇ ySsulfanyl ⁇ enzylJ ⁇ methyj ⁇ amine to a human patient in need thereof.
- a further aspect of the invention relates to use of 5-HTP and 2-(6-Fl ⁇ oro- 1 H-indo! ⁇ 3-ylsulfany!-benzyl]-methyl-amine for the preparation of a pharmaceutical composition for the treatment of diseases or disorders responsive to the therapeutic effect of an SRI.
- the invention in another aspect, relates to use of 5-HTP for the preparation of a pharmaceutical composition for the treatment of an individua! to be treated with or undergoing treatment with an SRI, wherein said individua! suffers from diseases or disorders responsive to the therapeutic effect of an SRI.
- the invention relates to use of 5-HTP for the preparation of a kit for the treatment of an individua! to be treated with or undergoing treatment with an SR!, wherein said individual suffers from diseases or disorders responsive to the therapeutic effect of an SR!.
- Diseases or disorders responsive to treatment with an SRS include, but are not limited to affective disorders, eating disorders, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, and drug abuse.
- Affective disorders include, but are not limited to depression and anxiety disorders. Eating orders inciude, but are not limited to bulimia, anorexia and obesity.
- Anxiety disorders include, but are not limited to general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder, and socia! anxiety disorder.
- the invention re!ates to a method for augmenting and/or providing an earlier onset of the therapeutic effect of an SRl comprising administering 5-HTP to a human patient to be treated with or undergoing treatment with an SRI.
- the pharmaceutical compositions as described herein are used in the treatment of depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, and drug abuse, in particular depression.
- the pharmaceutical compositions as described herein are used in the treatment of anxiety disorders such as generai anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder, or social anxiety disorder.
- anxiety disorders such as generai anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder, or social anxiety disorder.
- mice Male NMRI/BOM mice (18-25 g; Bomholtgaard, Denmark) may be used. The mice are housed in plastic cages (35 x 30 x 12 cm), 10 in each and habituated to the anima! facilities for at least a week before test. The room temperature (21 +/- 2° C), relative humidity (55 +/- 5%), and air exchange (16 times per h) are automatically controlled. The animals should have free access to commercial food pellets and tap water before test. A mouse that is forced to swim in a spatially constrained container wii! exert a characteristic immobile posture. Pretreatment with an antidepressant will counteract this effect. The test was conducted as described in detail by Sanchez and Meier ⁇ Psychopharmacol.
- mice Thirty minutes after drug or vehicle treatment the mice are treated with 5- HTP and 20 min later the mice are placed into the giass jar and left in the water for a total of 6 min. The accumulated duration of immobility is measured during the last 3 min.
- Microdialysis in freely moving rats may be performed as described in detail by M ⁇ rk, A,, Kreilgaard, M. and Sanchez, C. (Neuropharmacology, 2003 Aug, 45(2)- 167-73) to study the effect of escitalopram and fluoxetine alone, and in combination with 5-HTP (25 mg/kg, s.c.) on extracellular serotonin levels.
- mice Male Sprague-Dawley rats are prepared for microdialysis by surgically implanting intracerebral guide cannulas A micr ⁇ diatysis probe is inserted through the guide cannula. Perfusion of the microdiaiysis probe with filtered Ringer solution (146 my NaCI, 3 mM KCI, 1 mM MgCI 2 . 1.2 mM CaCIa) is done before the insertion of the probe and continued for the duration of the experiments at a constant flow of 1 ⁇ l/minute into the frontal cortex. After stabilization of the animals, testing is initiated by the injection of the compound of Formula iS. A 20 minute sampling regime may be used throughout the experiment. 5-HTP (25 mg/kg, s.c.) is injected 80 minutes following injection of the compound of Formula Si. 5-HT levels in the dialysate are measured in each sample by means of HPLC with electrochemical detection.
- mice Male BALB/cByJ mice (Jackson labs, Bar Harbor, ME) are housed 5/cage upon arrival, at which time they may be 7-8 weeks of age. Animals are acclimated to the housing facility under standard laboratory conditions for a period of at least one week before testing (lights on at 8:00 AM).
- mice Following a one hour period of acclimation to the test room, animals are dosed with either vehicle (saline) or the compound of Formula II. Thirty minutes later, animals receive an injection of vehicle or 5-HTP (2.5 mg/kg, i.p.). Fifteen minutes after the second injection, animals are individually placed into novel cages in which a layer of Aspen Pine bedding on which two parallel rows of 10 marbles each (i.e. twenty total) are placed. After 30 minutes elapse, the mice are removed from their test cages and returned to their home cages. The number of fully visible marbles (less than 2/3 covered with bedding) are counted and subtracted from 20 to arrive at the number of marbles buried.
- vehicle saline
- 5-HTP 2.5 mg/kg, i.p.
- Gannat, FRANCE Gannat, FRANCE weighing 250 to 300 g at the day of the experiment and which have been kept under standard laboratory conditions (12:12 light- dark cycle with free access to food and water).
- the anirnaSs were anesthetized with chloral hydrate (400 mg/kg, i.p.). Supplemental doses were given to maintain constant anesthesia and to prevent any nociceptive reaction to a tail pinch.
- Extracellular unitary recordings of dorsal raphe 5-HT neurons were performed with single-barreled giass micropipettes preioaded with fiberglass filaments in order to faci ⁇ fafe filling. The tip was broken back to 2 to 4 ⁇ m and filled with a 2M NaCI solution saturated with Blue Chicago dye.
- the rats (control or treated) were placed in a stereotaxic frame and a burr hole was drilled on the midline 1 mm anterior to lambda.
- Dorsal raphe 5-HT neurons were encountered over a distance of 1 mm starting immediately below the ventral border of the Sylvius aqueduct. These neurons were identified using the criteria of Aghajanian (Aghajanian, G. K., Essays Neurochem Neumpharmacol 2000, 3: 1-32); a slow (0.5-2.5 Hz) and regular firing rate and long-duration (0.8-1.2 ms) positive action potentials.
- WAY-100635 which is a selective 5 ⁇ HT 1A antagonist, increases the spontaneous firing rate of the neuron, suggesting that feedback inhibition of 5-HT neuronal firing has been decoupled by blocking 5-HTu receptors.
- the aSlosteric site of a protein is an additional binding site, which is distinct from the primary ltgand binding site.
- Compounds that modulate, for instance increase and/or stabilize, binding between the ligand and the iigand binding site are generally considered to operate through an aSlosteric mechanism.
- the serotonin transporter is considered to have at least two separate binding sites; a primary, high-affinity binding site that mediates the inhibition of serotonin reuptake, and one or more low-affinity binding sites that allostericaily modulate the binding of ligands at the primary site (PSenge. P., and Meiferup, EX Eur J Pharmacol. 1985 Dec 10; 119 ⁇ 1-2):1-8; W ⁇ nnogle, LP. and Meyerson, LR. Life Sd, 1985 Apr 22; 36(16): 1541 -50).
- Sertraline, fluoxetine, venlafaxine, and duloxetine had Sittie or no stabilizing effect on their binding to the primary binding site on the serotonin transporter (Chen, F., et a!., Eur Neuropsychopharmacoi. 2005 Mar; 15(2); 193-8).
- Dissociation binding experiments measure the "off rate" (k Of 0 for a radioligand of the protein. After radioligand and transporter protein are allowed to bind (i.e. form a complex), then ligand is added to block further binding of radbiigand to the transporter so that the rate of dissociation can be measured. Binding (as measured by radioactivity of the radioSigandiransporter complex) is measured at various times to determine the rate at which the radioligand dissociates from the transporter, Dissociation rate constants can be used to determine the half-life of the bound complex.
- Half-life determinations can be used to ascertain whether a compound is an aliosteric modulator of the human SERT.
- dissociation binding studies as similarly described in Chen, FC.entend J.Neurocbem, 2005, 92, 21-28, it was determined that the compound 2-( ⁇ -Fluoro ⁇ 1H ⁇ indoS-3 ⁇ ylsulfanyi) ⁇ benzyl]-methyi-amine binds to an alS ⁇ sferic site of SERT with an IG $ ⁇ of 26 uM and significantly siowed the dissociation rate of 3 H-escita!opram.
- isolated membranes from CGS-1 cells transiently transfected with hSERT (GenBank Accession. No. X70697) are prepared by standard methods. Methods of transfection are also well known in the art. Hereinafter, assays are carried out in duplicate from at least three independent transfections using the same transfection method.
- a radioligand/hSERT complex is formed during a 30-minute incubation of membrane preparations expressing hSERT and radioligand (radiolabeled-test compound) at 4 0 C in buffer (50 mM Tris, pH 7.4; 120 mM NaCI, 5rnM KCi). Radioligand is present at a concentration approximately 10 times the Kd value for the radioligand. (K ⁇ values are previously determined in the same buffer).
- the radioligand/hSERT complex is diluted by 30-fold in the same buffer, In separate experiments the radioligand/hSERT complex is diluted by 30-fold in the same buffer containing test compound (cold, non-radiolabeled). Incubation of the radiofigand/hSERT complex diluted in buffer with or without test compound continues for increasing time intervals at 20 0 C. At each time interval (e.g. 10 min., 20 min., 30 min., etc.), samples are removed from the incubation and the reaction is stopped by filtration through GF/C gSass-fiber filters on a DC! harvester. Accumulated radioactivity for each sample is determined by direct counting of plates using a Packard Bell microplate scintillation counter.
- the radioactivity represents binding and is expressed as fmof complex/mg membranes. Binding for each sample is plotted against increasing time to determine dissociation rate.
- the dissociation rate of the radioligand (k O f f ) is determined by non-linear regression using a GraphPad PRISM program ⁇ GraphPad Software, San Diego, CA).
- Dissociation half-life (Ua) is calculated by 0.69302/k off and is represented in units of time.
- Dissociation half-life of radioligand/hSERT complex (expressed in minutes) is plotted against increasing concentration of test compound in dissociation buffer (e.g. 10 ⁇ M, 20 ⁇ M, 30 ⁇ M, 40 ⁇ M, and 50 ⁇ M of test compound).
- dissociation buffer e.g. 10 ⁇ M, 20 ⁇ M, 30 ⁇ M, 40 ⁇ M, and 50 ⁇ M of test compound.
- the slope of this plot is termed a Z-factor.
- the Z-factor is calculated from at least four independent determinations.
- Z-factor is a measure of the degree of stabilization of the radioligand/hSERT complex.
- a Z-factor greater than 0 (zero) is indicative of a positive allosteric modulator.
- R-cttalopram does not fall within the class of SRIs, and is therefore not considered an alloste ⁇ c SRi, because R-citalopram binds to the primary binding site of the serotonin transporter having a reported IC 5 0 value of greater than 50 nM. See, for example, Sanchez, C, et al. Psychopharmacology 2003;
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Child & Adolescent Psychology (AREA)
- Addiction (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US97459507P | 2007-09-24 | 2007-09-24 | |
PCT/US2008/077435 WO2009042632A2 (en) | 2007-09-24 | 2008-09-24 | Combination therapy related to serotonin dual action compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2205238A2 true EP2205238A2 (en) | 2010-07-14 |
EP2205238A4 EP2205238A4 (en) | 2010-10-06 |
Family
ID=40512095
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08833434A Withdrawn EP2205238A4 (en) | 2007-09-24 | 2008-09-24 | Combination therapy related to serotonin dual action compounds |
Country Status (6)
Country | Link |
---|---|
US (1) | US20100286226A1 (en) |
EP (1) | EP2205238A4 (en) |
JP (1) | JP2010540461A (en) |
CN (1) | CN101868233A (en) |
CA (1) | CA2700199A1 (en) |
WO (1) | WO2009042632A2 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009538117A (en) * | 2006-03-22 | 2009-11-05 | ハー・ルンドベック・アクチエゼルスカベット | Methods for identifying compounds for treating depression |
WO2012054815A1 (en) * | 2010-10-22 | 2012-04-26 | Duke University | Slow-release formulations of 5-hydroxytryptophan as an adjunct to pro-serotonergic therapies |
US11464756B1 (en) | 2017-05-19 | 2022-10-11 | Jerry Darm | Mecuna pruriens, L-DOPA and 5-HTP based dietary supplements, pharmaceutical formulations and uses thereof |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3932652A (en) * | 1972-06-30 | 1976-01-13 | Hoffmann-La Roche Inc. | Antidepressant compositions |
US4329356A (en) * | 1980-10-31 | 1982-05-11 | Eli Lilly And Company | Treatment of hypertension with fluoxetine and l-5-hydroxytryptophane |
US4413012A (en) * | 1981-06-01 | 1983-11-01 | Merrell Toraude Et Compagnie | Method for treating depression |
US4596807A (en) * | 1985-03-26 | 1986-06-24 | Serotonin Industries Of Charleston | Method and compositions for controlling pain, depression and sedation |
US4698342A (en) * | 1985-07-16 | 1987-10-06 | Serotonin Industries Of Charleston | Method and compositions for controlling pain, depression and sedation |
US5668117A (en) * | 1991-02-22 | 1997-09-16 | Shapiro; Howard K. | Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments |
US5958429A (en) * | 1996-08-16 | 1999-09-28 | Eli Lilly And Company | Potentiation of serotonin response |
US6207699B1 (en) * | 1999-06-18 | 2001-03-27 | Richard Brian Rothman | Pharmaceutical combinations for treating obesity and food craving |
US6403657B1 (en) * | 1999-10-04 | 2002-06-11 | Martin C. Hinz | Comprehensive pharmacologic therapy for treatment of obesity |
US20020147153A1 (en) * | 2001-02-14 | 2002-10-10 | Functional Foods, Inc. | Nutritional supplement to alleviate symptoms associated with reduced levels of serotonin |
US20040197377A1 (en) * | 2003-04-03 | 2004-10-07 | Thompson Marshall Anlauf | 5-HTP composition |
PT1701940E (en) * | 2003-12-23 | 2008-07-30 | Lundbeck & Co As H | 2-(1h-indolylsulfanyl)-benzyl amine derivatives as ssri |
WO2005112906A2 (en) * | 2004-05-21 | 2005-12-01 | Duke University | Method for augmenting the effects of serotonin reuptake inhibitors |
AR054394A1 (en) * | 2005-06-17 | 2007-06-20 | Lundbeck & Co As H | DERIVATIVES OF 2- (1H-INDOLILSULFANIL) -ARIL AMINA |
US20070213370A1 (en) * | 2005-11-18 | 2007-09-13 | H. Lundbeck A/S | 5-HTP Combination Therapy |
US20070117844A1 (en) * | 2005-11-18 | 2007-05-24 | Morillo Connie S | 5-HTP combination therapy |
JP2009538117A (en) * | 2006-03-22 | 2009-11-05 | ハー・ルンドベック・アクチエゼルスカベット | Methods for identifying compounds for treating depression |
-
2008
- 2008-09-24 US US12/679,789 patent/US20100286226A1/en not_active Abandoned
- 2008-09-24 WO PCT/US2008/077435 patent/WO2009042632A2/en active Application Filing
- 2008-09-24 CA CA2700199A patent/CA2700199A1/en not_active Abandoned
- 2008-09-24 JP JP2010526063A patent/JP2010540461A/en active Pending
- 2008-09-24 CN CN200880118145A patent/CN101868233A/en active Pending
- 2008-09-24 EP EP08833434A patent/EP2205238A4/en not_active Withdrawn
Non-Patent Citations (2)
Title |
---|
No further relevant documents disclosed * |
See also references of WO2009042632A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO2009042632A3 (en) | 2009-05-14 |
EP2205238A4 (en) | 2010-10-06 |
WO2009042632A2 (en) | 2009-04-02 |
CA2700199A1 (en) | 2009-04-02 |
JP2010540461A (en) | 2010-12-24 |
CN101868233A (en) | 2010-10-20 |
US20100286226A1 (en) | 2010-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11241429B2 (en) | Method of treating metabolic disorders and depression with dopamine receptor agonists | |
Marcos et al. | Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension | |
RU2467743C2 (en) | Therapeutic treatment of metabolic syndrome, type 2 diabetes, obesity or potential diabetes | |
Taciak et al. | Drugs which influence serotonin transporter and serotonergic receptors: pharmacological and clinical properties in the treatment of depression | |
US20020103249A1 (en) | Combination of a serotonin reuptake inhibitor and irindalone | |
US20120258984A1 (en) | 5-htp combination therapy | |
US20190314301A1 (en) | Combinations of adrenergic receptor agonists for the treatment of type 2 diabetes | |
US20070117844A1 (en) | 5-HTP combination therapy | |
PT759299E (en) | SEROTONIN RESPONSE POTENTIATION | |
EP2205238A2 (en) | Combination therapy related to serotonin dual action compounds | |
MX2007009136A (en) | Organic compounds. | |
US20090176857A1 (en) | Use of Organic Compounds | |
Lambru et al. | Serotonergic agents in the management of cluster headache | |
Du et al. | Clinically relevant concentrations of ketamine inhibit osteoclast formation in vitro in mouse bone marrow cultures | |
WO2008035177A2 (en) | Combination of mt1 and mt2 melatonin receptor agonists and a norepinephrine/dopamine reuptake inhibitor | |
KR20100014081A (en) | 5-htp combination therapy | |
US9265774B2 (en) | Methods, compounds and pharmaceutical compositions for treating anxiety and mood disorders | |
MX2008016138A (en) | 5-htp combination therapy | |
KR20060072127A (en) | The combination of a serotonin reuptake inhibitor and loxapine | |
US8614247B2 (en) | Methods for preventing, attenuating or treating pulmonary hypertension using a serotonin transporter inhibitor, and pharmaceutical compositions for the treatment thereof | |
Elisabeth et al. | Serotonin Transporter Inhibitors Protect against Hypoxic Pulmonary Hypertension | |
Setola et al. | The Emergence of 5-HT 2B Receptors as Targets to Avoid in Designing and Refining Pharmaceuticals | |
WO2004089348A2 (en) | Use of a serotonin transporter inhibitor for the treatment of pulmonary hypertension | |
Setola et al. | The as Targets Emergence to Avoid of 5-HT in Designing | |
De Maeyer | Organ-dependent efficacy of 5-HT4 receptor agonists: a pharmacological and molecular study on porcine atrium and stomach |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20100426 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA MK RS |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20100906 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 25/24 20060101ALI20100831BHEP Ipc: A61P 25/22 20060101ALI20100831BHEP Ipc: A61K 31/405 20060101ALI20100831BHEP Ipc: A61K 31/404 20060101AFI20100413BHEP |
|
DAX | Request for extension of the european patent (deleted) | ||
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 25/22 20060101ALI20121107BHEP Ipc: A61K 31/405 20060101ALI20121107BHEP Ipc: A61K 31/404 20060101AFI20121107BHEP Ipc: A61P 25/24 20060101ALI20121107BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20130403 |